Date: 05 Jun 94 09:58 PDT
From: "John S. James"
AIDS TREATMENT NEWS Issue # 200, June 3, 1994
phone 800/TREAT-1-2, or 415/255-0588
CONTENTS:
Antivirals and Immune Recovery: Interview with Michael S.
Saag, M.D.
D4T (Stavudine): Approval Recommended
Government AIDS Research: the ACTG. Interview with Michael S.
Saag, M.D.
***** Antivirals and Immune Recovery: Interview with Michael
S. Saag, M.D.
by John S. James
Michael S. Saag, M.D., is Associate Professor in the Division
of Infectious Diseases at the University of Alabama at
Birmingham. He is both a laboratory scientist and a physician
who treats patients. "I combine my laboratory experience and
my clinical experience, and participate as a member of a
dynamic scientific group here at the University of Alabama at
Birmingham, where I help translate what's happening in the
lab and what's happening in the clinic, so the clinical and
laboratory groups can communicate efficiently. We are trying
to coordinate new developments in the laboratory with
clinical care and apply the developments to patients as soon
as possible."
Dr. Saag's group has done some of the earliest work with L-
524, the Merck & Co. protease inhibitor, a new anti-HIV drug
which is now in small-scale clinical trials. He is finding
evidence that the immune system can recover on its own to a
surprising degree, even from late-stage AIDS -- if the virus
can be suppressed enough, as measured by experimental blood
tests.
AIDS Treatment News: In a time of widespread pessimism, you
have said that there are important grounds for hope.
Dr. Saag: Much of the pessimism among HIV patients and their
physicians accelerated a little over a year ago, as the
Concorde data [questioning early use of AZT] started to be
discussed. I saw people get hung up on the details of a
single study, and lose sight of the big picture.
In the big picture, this is a viral disease. The virus
constantly wants to replicate, and the immune system tries to
suppress replication. The use of antiretrovirals helps
suppress the virus, but to date, the available agents are
effective for a limited time. The good news is that we have
learned a lot about HIV in less than a decade. We can target
specific elements of its life cycle to attack with antiviral
therapy. We can test new approaches [for example, protease
inhibitors] in the laboratory and find that they work; now we
are beginning to test them in people and find that they work
quite well, at least so far. The fact that we can figure
these things out is quite a testimony to basic sciences being
applied to clinical medicine. This is unprecedented in the
history of treating infectious diseases, where discoveries
are usually made by lucky accident, rather than by a reasoned
approach to drug development.
And now we have newer techniques to measure how well these
drugs work; we can follow the viral burden, as measured by
circulating RNA levels of the virus. We need more research to
be sure that tests not only tell us that the drugs are
active, but also translate into clinical benefit. Then we can
use the tests to tell us which drugs are working best in a
specific individual. If we can achieve that, it will be a
real step forward, and we will be great shape in the next two
or three years.
ATN: Is the P24 antigen test not very effective?
Saag: It could be OK if someone has a level that is
measurable. But for the majority who are not p24 positive, or
for those who are marginally positive and convert to
negative, you cannot tell how well the drugs are working and
how long their effect lasts. I think the HIV RNA is a much
more direct marker in people; I believe that ultimately it
will be proven to be useful in day-to-day practice.
ATN: What needs to be done to get more certainty, and to make
these tests more widely available?
Saag: We need to show that the tests correlate to clinical
outcome. That is easy to say and hard to do.
One approach would be a retrospective study -- a case-
controlled evaluation of a known cohort. We could use stored
specimens from previously conducted trials, and select
specifically those individuals who had disease progression,
and compare them with those who did well on the study. This
might require several hundred patients over many time points.
Then we will see if these tests can indeed predict who is
going to do well. Other studies may prospectively evaluate
the marker, allowing those with a poor prognosis to keep
trying different treatments until the tests show that the
prognosis has improved.
It has been shown that CD4 counts (T-helper counts) can show
indirectly whether or not an antiviral drug is working. But
they are not good at telling us precisely what is going to
happen to an individual clinically. That has always been a
problem in comparing drugs; first, because existing drugs
were not powerful enough to make profound changes in T-helper
counts and immune system restoration, and secondly, because
there is much variability in the measurement of the counts.
T-helper counts are still useful, but not as good as they
need to be. These new blood tests (for levels of HIV RNA) may
fine-tune the measurement so we can predict how someone is
going to do clinically.
ATN: Has early experience with the protease inhibitor L-524
shown that, if you can suppress the viral load, there is
evidence of immunological and clinical improvement?
Saag: AZT seems to do this as well, but to a smaller degree.
If you reduce viral burden by ten fold, with AZT, you'll see
an increase in T-helper counts, but not a profound increase.
They may go up from 50 to 100, for example, or 100 to 200.
But it seldom does much better than that, and the durability
of the increase is about six to 12 months, if you start later
in the course of the disease. If you start earlier, for
example with baseline counts of 400 to 500, the durability
may be 18 to 36 months.
With the protease inhibitor L-524, we have seen some examples
of viral burden dropping around 100 fold. When we achieve
that, we can see at least temporarily a substantial increase
in T-helper counts -- in some cases from below ten, to around
the 200 range, lasting for several weeks or months. This is
important because it is proof of concept that the protease
inhibitors indeed can work, and that they mirror what we
hoped to see from the test-tube experience. Also, it shows
that if you can suppress viral replication to a more profound
degree than with AZT, then the immune system has some ability
to reconstitute itself, at least as measured by the T-helper
count. To a degree we knew that from AZT; now, with new
agents which may be more potent than AZT, we are seeing more
immune system reconstitution as a natural consequence of
reduced viral replication. [So far the effect is temporary,
however, since HIV develops resistance to the drug, and then
the viral load increases.]
The recent experience with L-524 and other antiviral drugs
has been telling us a lot about viral pathogenesis. The virus
is becoming easier to understand in terms of what it is
trying to do -- to survive and replicate. It is constantly
trying to infect new cells, and to turn itself over [replace
the current virus with new generations]. This suggests that
ideally we should be treating patients as early as possible.
Whether people believe that AZT is good enough to begin
therapy when T-helper counts are above 500 remains to be seen
in clinical trials. But if we could imagine drugs that are
two, three, or ten times better than AZT, then I don't think
there would be much of a debate. If they are relatively
nontoxic, we will be using the drugs as early as possible.
ATN: We heard about one person who started L-524 with a T-
helper count of 600, and had a large increase which continued
even after the drug was stopped.
Saag: One patient was in our earlier studies, when we just
treated patients for 12 days. He had a T-helper count in the
600 range, and it did go up to over 1000. He only had 12 days
of therapy, and he stayed around 1000; he is still there at
this time (12 months later). I can't say that this was due to
the L-524, but it is a possibility. If we consider that this
is a virus that is constantly trying to replicate, when you
give antiviral therapy, you're adding air support for the
infantry; perhaps using a drug with that much activity early
in the course of disease may have allowed his immune system
to get a better handle on the viral infection, and gain
better control -- having effects even long after the drug was
present.
The other possibility is that the T-helper increase would
have happened anyway, due to variability in the expression of
the disease. But usually one would expect that T-cell counts,
left to their own devices, would continue to drift downward,
not bounce up by 400 cells per cubic millimeter.
ATN: It would make a lot of sense to try this treatment with
a few more patients, and see if it happened again.
Saag: I think so. We should do it in a controlled way,
following people with that goal in mind. Remember that in the
early studies with this compound, all we were really looking
for was safety and the pharmacokinetic profile; what happened
to the patients clinically was more of an incidental
observation; we were certainly interested in it, but that was
not an objective of the study.
We need more research on earlier infection. Indeed there are
some trials in development right now, not so much with
protease inhibitors just yet, but with some of the nucleoside
analogs [e.g. AZT, ddI] and non-nucleoside reverse
transcriptase inhibitors [e.g. nevirapine, or delavirdine],
looking at earlier interventions to see what antiviral
effects we get in people with higher T-helper counts.
ATN: The big interest now is combination treatments, for
delaying or avoiding resistance; this has worked for other
diseases. Is there anything you can add from your work? What
combinations would make sense to test with L-524?
Saag: The results so far with the Merck drug (L-524) are all
with monotherapy [the drug alone, not in a combination].
Roche is finding some success with their protease inhibitor
in combination with AZT. So the first approach would be to
use the protease inhibitors with AZT. The rationale is that
you're attacking two different areas of the viral life cycle;
that is sound reasoning.
Another approach would be to combine a protease inhibitor
with other nucleoside drugs that have different toxicity
profiles [for example, ddI], or perhaps with non-nucleoside
drugs, such as nevirapine.
We may also want to try combining different protease
inhibitors. The resistance patterns for the different
protease inhibitors are different. After growing HIV in cell
culture in the laboratory [with low doses of a protease
inhibitor, to deliberately produce resistant viruses],
resistant or less susceptible viruses can be identified, and
they have certain changes in their genetic structure that
confer the resistance. If you do this with another drug, you
get a virus which is less susceptible to that drug, but often
not less susceptible to the first drug; there may be little
or no cross resistance. The reason is that different changes
in the genetic makeup of the virus give resistance to the
different drugs.
So if you have the two drugs together in the same patient,
you might have broader coverage against the two types of
genetic changes that could occur, just using protease drugs.
That may work well in the future. But first we must prove
that the new drugs are safe and well tolerated, and that the
drugs being combined do not have harmful interactions. If
they can be safely administered together, a combination test
will be important.
***** Government AIDS Research: the ACTG. Interview with
Michael S. Saag, M.D.
by John S. James
[Note: This interview was conducted as a continuation of
"Antivirals and Immune Recovery," above.]
Michael S. Saag, M.D., a researcher at the University of
Alabama at Birmingham, is a new member of the Executive
Committee of the AIDS Clinical Trials Group (ACTG), the main
U.S.-government program for clinical trials of AIDS drugs.
Among other responsibilities, Dr. Saag directs the
subcommittee in charge of the ACTG's interaction with outside
groups, including the pharmaceutical industry, community
organizations, and government medical-research teams outside
the ACTG.
ATN: What is most important for our readers about the ACTG?
Saag: I think the ACTG is a very valuable resource for the
country. It has taken a lot of criticism, some of it fairly
applied. But the success of the ACTG is not widely
understood.
If you think about what happens in clinical practice today in
a doctor's office, and compare it to six or seven years ago,
you will find that much -- perhaps 70 to 80 percent of the
activities of a physician, in terms of new approaches to
management of their HIV patients -- was initiated through the
results of an ACTG trial. When you go to conferences, and
hear discussions about patient care and trial results, you
almost always hear references to ACTG studies. There have
been many contributions, not only in the primary infection
area [treating HIV itself], but especially in opportunistic
infectious diseases. What types of prophylaxis work best,
what is the best treatment for cryptococcal meningitis or
pneumocystis pneumonia or CMV retinitis, these results have
usually come from ACTG trials. People should recognize that
the ACTG has made major contributions.
Also, much that goes on behind the scenes at the ACTG helps
pharmaceutical-industry studies. Consider the quality
assurance program that assures that virology labs working
with the ACTG all operate in a standardized way, and that the
measurements of T-cell counts are standardized. All these
spill over into industry trials. The sites that are ACTG
funded also can do industry studies, and whenever a company
goes to those sites, it is using the same laboratories that
are ACTG certified. That's been a very important plus for
studies that are not ACTG affiliated.
In the future, due to a recent reorganization, the work of
the ACTG will be based more directly on a foundation of its
scientific agenda. In the past, an individual researcher at
an ACTG site would come up with an idea, propose it as a
concept sheet, and go through the system from the bottom up.
While that is democratic and taps into the great resources of
a number of very talented people, it can also be inefficient.
In the future, all these researchers with their talents and
ideas will first come together to brainstorm and come up with
a scientific agenda, and then develop specific protocols to
address that agenda. This should speed protocol development
and the conduct of trials.
ATN: We have heard of many cases where concept sheets don't
go anywhere, probably because the leadership does not agree
with them. This change might help to avoid that problem.
Saag: I think it will. And I think the other problem is that
some members of the ACTG, especially in leadership positions,
get so inundated with paper, having to keep up, that it's
hard to give every concept sheet a clean, fresh look every
time. You never know when one is going to be coming in.
So we will back up and say, "What are the big-picture issues
that we should be addressing as a group?" We will define
those questions, establish that agenda, prioritize, and then
ask, "What kind of trials will help us answer this question?"
I believe that the proposal I have seen will reduce protocol
development time -- going from an idea to a protocol open for
enrollment -- from over 230 days down to about 85 days. This
is about to be implemented.
Also, we also should keep in mind what would happen if the
ACTG did not exist. Suppose it had never been created; what
would people be saying about what ought to be done? They
would say that we should get together some of the best
scientists and clinical investigators in the country, and
form a network where they could work together and study new
approaches to treat the disease. Also, you would want to
bring those people together, at least semi-annually, to talk
about progress, discuss current issues, decide directions
together, and then implement those new protocols and studies
that they come up with. That is precisely what the ACTG is.
The problem is that it has been inefficient in its ability to
get things done quickly; it has been too bureaucratic in the
past. I think that with the reorganization it will become
more streamlined, and enable us to fulfill those desperately
needed missions of having some of the better investigators in
the country working together on joint projects.
I'm very encouraged by what is happening. There is a dynamic
interaction within the ACTG leadership, and a lot of
dedication to making the organization run efficiently, and be
as productive as possible. I'm optimistic that we can do
that. But it will take much work to get us to that next
level.
ATN: Recently some leading scientists have called for a
redirection of AIDS research. [See "AIDS Research Direction:
New Scientific Approach?," AIDS Treatment News #199, May 20,
1994.] Some have interpreted Dr. Fields' recent paper as
calling from a shift from clinical to basic research; but
what he really seems to be saying is that there should be
better communication between the laboratory studies and the
clinical trials which test new drugs in patients. Where do
you think we should focus now?
Saag: There has been a fairly strong emphasis on basic
science from NIAID [the U.S. National Institute of Allergy
and Infectious Diseases, which runs the ACTG] over the last
five or six years. In 1987, there was a project called
Programs for Excellence in Basic Research on AIDS (PEBRA);
our team at the University of Alabama was one of the
recipients of that award, and that is what started us
coordinating the clinical side and the basic science side.
That's the kind of initiative we should continue with.
NIAID has continued this approach, with the new SPIRATS
grants, which encourage investigators to work together from
the beginning of a new concept of treatment, to developing
that approach in the laboratory, and carrying it through all
the way to the initial clinical trials. [Note: SPIRATS stands
for Special Program for Innovative Research on AIDS
Treatments. The first five to eight SPIRATS grants are
expected to be awarded in August 1994.] This is an important
initiative that encourages creativity among investigators
within different disciplines, having them work together.
This kind of approach is where progress in HIV will come
from. I think we do it at the University of Alabama about as
well as it's done anywhere; it was the U.S. National
Institutes of Health programs that got us going. The PEBRA,
our Center for AIDS Research, and other government programs,
have all been used to have scientists from different
disciplines work together. This is the critical issue that
should be emphasized, rather than segregating out more money
for basic science, or for clinical science. We are trying to
get money used in a way that maximizes the interaction
between the different disciplines and different research
groups.
***** D4T (Stavudine): Approval Recommended
by John S. James
The experimental anti-HIV drug d4T (generic name stavudine,
brand name Zerit), now widely available in a "parallel track"
program for patients who cannot successfully use either of
the approved drugs AZT or ddI, was cautiously recommended for
early approval by the Antiviral Drugs Advisory Committee, at
an all-day public hearing on May 20. The FDA [U.S. Food and
Drug Administration] must make the final decision on whether
to grant approval on the basis of the data so far available;
it does not have to follow the recommendation of its advisory
committee, but usually does.
There has been considerable confusion about this hearing and
what it means. We believe that most of the confusion does not
involve d4T itself. Rather, it arises from the difficulty of
fitting the particular situation of this drug into the
existing body of approval regulations, in such a way that a
reasonable result is achieved.
[Note: This writer did not attend the hearing. This report is
based on discussions with people who were there.]
Background
A major clinical trial of d4T (known as the '019' study) is
still underway in the U.S.; it is expected to finish at the
end of 1994. After completion of this trial, it will take
months to analyze the data and schedule another hearing of
the Antiviral Drugs Advisory Committee; as a result, approval
will be delayed for about a year if it is necessary to wait
for the final data and its analysis. To avoid this delay, the
developer of d4T, Bristol-Myers Squibb Company, asked for an
earlier approval under the new "accelerated approval"
regulations. These regulations allow the FDA to approve a
drug for serious or life-threatening illnesses, when no other
satisfactory treatment is available, on the basis of
"surrogate markers" (for example, blood tests such as the T-
helper count, which seems to provide a crude measure of a
drug's effectiveness). But the pharmaceutical company must
finish its clinical trials, in order to eventually obtain
conclusive proof that the drug is clinically beneficial to
patients.
D4T Results
The May 20 hearing focused on partial data from two human
studies of d4T. One is the Bristol-Myers '019' study -- the
ongoing clinical trial mentioned above. The other is the
parallel track program, run by Bristol-Myers with FDA
permission primarily for compassionate purposes, to make the
drug available before approval for persons with no other
therapeutic option.
The '019' study includes 822 patients. All of them had been
on AZT for at least six months (but often considerably
longer). When they entered the study, each patient was
randomly assigned to either continue AZT, or switch to d4T.
The study is "blinded"; neither the patients nor their
physicians were told who is getting which drug.
At the May 20 hearing, data was available for 359 patients.
Data from the other 463 patients could not be used, because
their treatment is still blinded. (Researchers are very
reluctant to break the blind prematurely, since doing so
could bias the study.)
About 14 percent of the patients in this study entered with a
T-helper count under 100. About 50 percent were in the range
of 100 to 300; and the other 36 percent were over 300. Only
10 percent had an AIDS diagnosis at entry.
The data showed that:
* Those assigned to d4T had an average rise to a maximum of
about 20 to 25 in their T-helper count, compared to baseline
(just before their d4T treatment began). Counts then
declined, however, and by week 16, the average increase from
baseline was only about 10. For those assigned to continue on
AZT, T-helper counts decreased. According to Bristol-Myers, a
difference of 50 in the T-helper count between groups was
maintained for up to 60 weeks.
* HIV titer (of PBMC-associated virus) dropped 53 percent
from baseline, for those on d4T. For those on AZT, the titer
increased 11 percent.
* The d4T group also showed improvement in weight gain over
the AZT group. The weight gain on d4T was small, however, and
there was no significant weight gain for those with T-helper
counts under 100. But the average difference between the d4T
and AZT groups exceeded 2 kilograms (4.4 pounds).
* In an interview with AIDS Treatment News, Lisa Dunkle,
M.D., who presented some of the data for Bristol-Myers at the
May 20 hearing, said that the d4T group showed hematologic
improvements over the AZT group. She did not present the
hematologic data at the hearing, however.
* According to Dr. Dunkle, there was also a marked difference
in favor of d4T in reduced side effects -- with the only
adverse event being peripheral neuropathy in 12 percent of
the patients after one year, and in only half of those was it
serious enough to require discontinuation of the drug. (See
other views of side effects, below.)
The data now available from the parallel-track program was
less clear. This program is only for patients who had already
tried and failed both AZT and ddI. As would be expected, they
tended to be at a more advanced stage of HIV infection; their
median T-helper count at entry to the parallel track was 41,
and 75 percent of these patients had a T-helper count under
100 (compared to only 14 percent for the '019' study, as
reported above).
In order to collect scientific data from this program,
patients were randomly assigned to two different doses of d4T
-- either the standard dose of 40 mg twice a day (the dose
used in the '019' study), or half that dose, 20 mg twice a
day. After a median time of 40 weeks, 79 percent of the
patients were still alive. As a check to make sure that
patients were not left on a dose known to be inferior, a
group called the Data Safety Monitoring Board (DSMB) secretly
unblinded the study and compared the two doses. It found that
there was no survival difference between the doses, but that
those taking the larger dose had a somewhat higher risk of
peripheral neuropathy -- 21 percent of those receiving 40 mg
twice a day, vs. 15 percent of those receiving 20 mg twice a
day. As a result, the DSMB asked that the 40 mg dose be
discontinued in the parallel track, and those who had been
receiving it were switched to 20 mg.
Since the survival rate was the same with the 40 mg and 20 mg
doses, does this mean that the two doses both worked equally
well -- or does it mean that the drug did not improve
survival for those patients at all? We cannot tell from the
parallel-track data. There was no placebo or no-treatment
group (which would have been unethical in this situation);
and it was also impossible to compare d4T with AZT or with
ddI, since the patients had to fail both of those drugs as a
condition for getting into the parallel track. (The '019'
study is designed to look for a survival difference --
between switching from AZT to d4T, vs. continuing on AZT --
so we should have information after this study is completed.)
Patients in the parallel-track program were not required to
obtain regular T-helper counts. Somewhat fewer than half of
them did choose to do so; and for them, T-helper counts
tended to be stable for over a year.
Regulatory Issues
There has been some confusion about just what the May 20
hearing did decide, and what it means. To understand the
current status of d4T, certain background should be kept in
mind:
* The studies are not comparing d4T against AZT (or against
ddI or ddC, the other approved anti-HIV drugs) as a starting
treatment. (Early, smaller studies evaluated d4T as a
starting treatment in some patients, and found that the T-
helper count rise appeared to last for a prolonged period --
but the large studies now ongoing are not designed to confirm
this result, or to make sure that it translates into clinical
benefit.) Also, there is no study comparing switching to d4T
vs. switching to ddI, as a second treatment after AZT. Nor is
there any comparison of d4T in combination with other anti-
HIV drugs. These obvious question, that doctors would like to
have answered, will not be addressed in the approval of d4T.
* Despite the limited information, and the disappointment due
to the small T-helper count improvement seen in the '019'
study, there is a widespread feeling that, on balance, d4T
should be approved -- without waiting an extra year for the
final data from the '019' study. Everyone knows that existing
HIV treatments are inadequate; and all the evidence suggests
that some people do benefit from d4T. At the same time, the
existing parallel track program restricts access to the drug,
and limits the normal development of clinical experience by
physicians. Bristol-Myers has provided this program as a
public service, at a cost of millions of dollars which it may
not be able to recover, instead of denying the treatment to
thousands of people. (But there is increasing concern that as
the overall process of drug development becomes more
expensive, other companies will avoid developing potential
AIDS drugs, and may even conceal important treatment leads.)
* The regulatory complication about approving d4T now is the
following. The FDA's new "accelerated approval" regulations
would need to be used, since the data so far shows
improvement in blood tests and in weight gain, but not in
"clinical endpoints"; there is not enough data yet to provide
statistical proof that, in the long term, certain patients
treated with d4T will do better than those treated otherwise.
The accelerated approval system was designed for just this
situation.
But the accelerated approval regulations require that no
other treatment be available; the point is to allow the
increased risk of approving a drug early, without clinical-
endpoint data, in situations where the need for the drug is
very urgent. This is the case with those in the parallel
track program, as they have already failed standard
treatments.
The complication is that while accelerated approval does
apply to one group of patients, the best data available are
from another group, those with less advanced disease (who are
in the '019' study). An additional complication is that the
dose which generally appears best and will probably be
approved, 40 mg twice a day, is the dose which the DSMB
discontinued for those in the parallel-track program -- the
patients that an accelerated approval will need to address.
In other words, there seems to be a general consensus that
d4T should be approved; but the factual situation of this
drug does not exactly match what the regulations were
designed for. The FDA staff seems to have sidestepped this
potential red-tape gridlock by asking the Advisory Committee
to answer particular questions which have the effect of
leaving the situation open. This gives the FDA staff more
freedom to make the right decision on the basis of all
available data, as it comes in, without needing to wait a
year for the '019' study to be completed.
The FDA asked the Antiviral Drugs Advisory Committee to vote
on the following questions:
"1. Does there exist a population for whom stavudine [d4T]
will provide meaningful therapeutic benefit over existing
therapies? If the answer is yes please comment on the
characteristics of that population.
"2. Has the applicant provided evidence from adequate and
well-controlled clinical trials establishing that stavudine
has an effect on a surrogate endpoint that is reasonably
likely to predict clinical benefit?"
The Advisory Committee answered yes to both questions, by
majority vote. This is considered a recommendation in favor
of approval.
Side Effects Controversy
Over a year ago ACT UP/Golden Gate, a San Francisco-based
activist group, started a series of public forums for people
in the d4T parallel-track program, independently of Bristol-
Myers or anyone else involved. ACT UP also developed a
survey, and its own computer database to record peoples'
reports, and was in phone contact with patients around the
country. In July 1993 ACT UP/Golden Gate reported that more
than half of the patients in its database had some degree of
peripheral neuropathy or other side effect that they thought
might be drug related. The organization presented an updated
version of its report at the May 20, 1994 hearing on d4T.
[Note: This writer usually attends the weekly meetings of the
ACT UP/Golden Gate Treatment Issues Committee. We were not
involved in the d4T study, however.]
A practical result from the ACT UP study is the suggestion
that, if people have sleep disturbances while taking d4T, the
problem can often be corrected by not taking the second dose
at bedtime, but taking it earlier in the day.
In addition, the Conant Medical Group in San Francisco did a
retrospective study of the case reports of about 100 of its
patients who participated in the d4T parallel track program;
it found that more than half of them reported adverse effects
which might have been drug related. While this study has not
yet been published, the Conant Medical Group sent a summary
report to the FDA before the May 20 meeting.
These numbers are considerably higher than those reported by
Bristol-Myers, and also by the DSMB. No one knows why there
is this difference. Self-selection may have had a large
effect on the ACT UP numbers, since those who have problems
during a treatment may be more likely to come to a meeting
and be recorded in the database. But self selection would not
be expected to have affected the Conant study.
The differences might also have occurred if Bristol-Myers and
the DSMB made more effort to screen out minor side effects or
those which appeared not to be drug related, while the other
reports counted everything. The major side effect of d4T is
peripheral neuropathy, which can also be caused by HIV
itself. This makes it hard to interpret reports of side
effects -- especially since the patients in the parallel-
track program usually had advanced AIDS or HIV infection,
which would have caused a number of cases of peripheral
neuropathy that were not due to the drug.
The issue of side effects should be kept in perspective. ACT
UP/Golden Gate, which first reported seeing a larger number
of side effects, still supported approval of d4T at the May
20 hearing -- but asked for neuropsychiatric studies focusing
on possible adverse effects of the drug. And the Conant
Medical Group is continuing to use d4T through the parallel-
track program. The issue of side effects will affect medical
management of d4T use, but it has not changed the belief that
the drug can be useful and should be available.
Comment
At the May 20 meeting, the FDA also asked the Advisory
Committee to meet again, on the subject of "surrogate
markers" in AIDS drug approval (for any drug, not focusing
only on d4T). This concerns the ongoing controversy of
whether we can trust blood tests such as T-helper counts, or
clinical indications such as weight gain, as proof that an
AIDS drug is really a benefit to patients.
On this issue, we believe it is time for AIDS community as a
whole -- as well as the FDA, and its advisory committee -- to
step back and take a look at the big picture. And the big
picture, we believe, is that far too much effort is being
spent agonizing over the details of marginal drugs which will
never work very well. Instead, we should quickly approve the
drugs when there is good safety data and some indication of
benefit. Then we can re-focus research attention and
resources on the discovery and development of fundamentally
better treatments.
AIDS TREATMENT NEWS
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AIDS Treatment News reports on experimental and
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and found combinations which work for them. AIDS
Treatment News does not recommend particular
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ISSN # 1052-4207
Copyright 1994 by John S. James. Permission granted for
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